Abstract: PO0724
Circulating SIRPα Is Upregulated in Type 2 Diabetes, Impairing Insulin Signaling in Skeletal Muscles and Adipose Tissues
Session Information
- Diabetic Kidney Disease: Basic - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Wu, Jiao, Baylor College of Medicine, Houston, Texas, United States
- Mitch, William E., Baylor College of Medicine, Houston, Texas, United States
- Thomas, Sandhya S., Baylor College of Medicine, Houston, Texas, United States
Background
A major etiology of chronic kidney disease (CKD) is diabetes mellitus. Even at early stages of CKD with near normal GFR, impaired insulin signaling is present, suggesting an early trigger of insulin resistance. We have discovered a potential driver of insulin resistance, signal regulatory protein alpha (SIRPα) which adversely influences skeletal muscles and adipose tissues in a model of type 2 diabetes.
Methods
Control mice vs. global SIRPα knockout (KO) mice were subjected to HFD >12 weeks. Glucose (GTT) and insulin tolerance tests (ITT), immunoblots, and treatment of myotubes with recombinant SIRPα were performed. n=4-6 mice/group, results are presented as mean ± SD.
Results
Control mice with HFD displayed impaired insulin signaling with reduced levels of tyrosine phosphorylation of the IGF1R, PI3 kinases and pAKT (ser473) in skeletal muscles. However, in SIRPα KO mice with HFD there was no downregulation of these insulin signaling proteins. Next, we examined adipose tissues of these mice and found impaired pAKT in control mice fed a HFD. In SIRPα KO mice pAKT signaling remained intact despite exposure to HFD. Next, control mice exposed to HFD displayed impaired GTT/ITT. However, KO mice had preserved GTT/ITT despite the presence of HFD. Finally, we identified a high level of serum SIRPα in control mice exposed to HFD. Therefore, we treated myotubes with exogenous recombinant SIRPα which led to downregulation of pAKT signaling.
Conclusion
Suppression of SIRPα in a HFD model of type 2 diabetes improves insulin resistance and is a potential therapeutic target for the treatment of type 2 diabetes.
Funding
- Other NIH Support